MITOCHONDRIAL INJURY - LESSONS FROM THE FIALURIDINE TRIAL

Fialuridine is an antiviral agent with potent activity against hepatit is B virus replication in vitro and in vivo. In a phase II study, 7 of 15 patients experienced severe toxicity due to the drug after 9 to 13 weeks of treatment. Adverse effects included nausea, vomiting and pai nful paraesthesia; subsequently, hepatic failure, pancreatitis, neurop athy, myopathy and lactic acidosis developed, probably due to multisys tem mitochondrial toxicity. Possible mechanisms of fialuridine toxicit y include mitochondrial injury and pyruvate oxidation inhibition. Whil e other nucleoside analogues have shown evidence of inducing mitochond rial injury (zidovudine, didanosine, zalcitabine), others to date have not (lamivudine, famciclovir). Specific recommendations for future st udy of existing and new nucleoside analogues include testing for toxic ity after prolonged incubation, specific investigations to measure mit ochondrial function, toxicological tests and well designed clinical tr ials with appropriate testing to monitor for any adverse effects on mi tochondrial integrity and function.